Genetic material once considered junk actually could hold key to cancer drug response

(New York, NY – April 3, 2018)–Material left out of common processes for sequencing genetic material in cancer tumors may actually carry important information about why only some people respond to immunotherapy, possibly offering better insight than the type of material that is being sequenced, according to a study by Mount Sinai researchers published on April 3 in Cell Reports.

Sequencing a type of genetic material in cancer tumors called messenger RNA has transformed personalized cancer therapy and revealed biomarkers for early detection. Advances in this field have transformed scientists' understanding of the differences between healthy tissue and tumors.

To date, gene expression in tumors has been typically profiled by capturing messenger RNAs; however, they represent only a fraction of the molecules detected. A different type of RNA, called non-coding RNA, had long been dismissed as "junk" and left out of sequencing processes. However, recent advances in genetics have shown that many non-coding RNAs can carry critical functions for cell biology, and a class of RNA known as repetitive elements may interact with the immune system in a way that may be important to develop new and personalized cancer immunotherapies.

In their study, the researchers used a process called total RNA sequencing to identify many non-coding RNAs that would normally remain undetected with the more common sequencing method. They showed that several of these RNAs were specifically expressed in tumors that responded to checkpoint blockade immunotherapy in bladder cancer patients, while others were associated with tumors that escaped being sensed by the immune system.

"Our conclusions make the case that non-coding RNA in tumors, particularly repetitive elements, is under-quantified," said the study's senior author, Benjamin Greenbaum, PhD, Assistant Professor of Oncological Sciences, Pathology, and Medicine (Hematology and Medical Oncology) at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai. "We feel that critical findings will arise from analysis of the full breadth of a tumor's non-coding RNA interplay with the immune system."

One specific finding of this study was that one repetitive element in non-coding RNA is a better predictor of immunotherapy response to PDL1 inhibitors, a type of cancer immunotherapy drug, than conventional immune signatures in certain patients. Mount Sinai researchers, in partnership with the Ting Lab at the Massachusetts General Hospital Cancer Center, found that these repeat RNAs appear to alter the immune response in colon and pancreatic cancers. These have implications for future research on how non-coding RNA could be novel targets for cancer therapy and how they influence patients' response to cancer therapies.

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Researchers from Massachusetts General Hospital and Memorial Sloan-Kettering Cancer Center played critical roles in this research.

This research was supported by grants from the Ludwig Center for Cancer Research, the National Institutes of Health(NIH)/National Cancer Institute Cancer Center Support Grant P30 CA008748, Stand Up to Cancer, the Lustgarten Foundation, the National Science Foundation Grant 1545935, NIH grant K12CA087723-11A1, the Burroughs Wellcome Fund, Affymetrix, Inc., NIH grant P01CA087497-1 and the V foundation.

About the Mount Sinai Health System

The Mount Sinai Health System is New York City's largest integrated delivery system encompassing seven hospital campuses, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai's vision is to produce the safest care, the highest quality, the highest satisfaction, the best access and the best value of any health system in the nation. The System includes approximately 7,100 primary and specialty care physicians; 10 joint-venture ambulatory surgery centers; more than 140 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. Physicians are affiliated with the renowned Icahn School of Medicine at Mount Sinai, which is ranked No. 18 for research by U.S. News & World Report's "Best Medical Schools" and No. 13 in the nation for National Institutes of Health funding. The Mount Sinai Hospital is ranked No. 18 on U.S. News & World Report's "Honor Roll" of top U.S. hospitals; it is one of the nation's top 20 hospitals in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Geriatrics, Nephrology, and Neurology/Neurosurgery, and in the top 50 in four other specialties in the 2017-2018 "Best Hospitals" issue. Mount Sinai's Kravis Children's Hospital also is ranked in six out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 12th nationally for Ophthalmology and 50th for Ear, Nose, and Throat, while Mount Sinai Beth Israel, Mount Sinai St. Luke's and Mount Sinai West are ranked regionally. For more information, visit http://www.mountsinai.org/, or find Mount Sinai on Facebook, Twitter and YouTube.

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